* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With 3-chloro-benzenecarboperoxoic acid In dichloromethane at -5 - 0℃; for 1.66667 h; Inert atmosphere Stage #2: With dimethylsulfide In dichloromethane at 0℃; Inert atmosphere Stage #3: With ozone In dichloromethane at -78℃; Inert atmosphere
To m-chloroperbenzoic acid (8.0g, 0.46 mmol 85percent) in dichloromethane(100 mL)(cooled to -5°C) was added a solution of S,S-dimethyl-N-(2-pyrazinyl)sulfilimine (5.36 g, 0.028 mmol) in 30ml dichloromethane dorpwise at such a rate for 1 hour with the temperature not exceed 0°C, the reaction mixture was stirred for another 40min at 0°C, The solution of dimethyl sulfide in dichloromethane was added at 0°C. Filltered quickly to afford a orange clean solution .The solution was cooled to -78°C, then 03 was bubbled into the mixture until the orange solution was turned to be colorless. The resulting suspension was quenched with sodium dicarbonate solution and then extracted with dichloromethane for three times. The combined organic phase was concentrated to afford the crude product, which was further purified by flash chromatography to afford 2-Chloro-3-nitro-pyrazine. (0.5 g, yield: 7percent).1HNMR (DMS0-
Reference：
[1] Journal of Heterocyclic Chemistry, 1983, vol. 20, # 4, p. 947 - 950
[2] Patent: US2006/47126, 2006, A1, . Location in patent: Page/Page column 25
[3] Patent: WO2011/5759, 2011, A2, . Location in patent: Page/Page column 69
[4] Patent: WO2013/78254, 2013, A1, . Location in patent: Paragraph 00349
2
[ 6863-73-6 ]
[ 144-55-8 ]
[ 86536-74-5 ]
[ 87885-43-6 ]
Yield
Reaction Conditions
Operation in experiment
79%
With dimethyl sulfoxide; trifluoromethanesulfonic acid anhydride In dichloromethane
EXAMPLE 1 3-Chloro-2-nitropyrazine STR11 Step A: S,S-Dimethyl-N-(3-chloropyrazin-2-yl)sulfilimine (2) To a mechanically stirred solution of 3.9 g (0.05 mol) dimethyl sulfoxide in 30 ml dry methylene chloride at -78° under nitrogen is added 13.1 g (0.046 mol) trifluoromethanesulfonic anhydride dropwise to afford a white precipitate. To this is added a solution of 5.0 g (0.039 mol) 2-amino-3-chloropyrazine (1) in 30 ml methylene chloride/15 ml dimethyl sulfoxide and the resulting solution is stirred at -78° for 2 hours and at -55° for 1 hour. The reaction mixture is then quenched with 50 ml of 5percent aqueous sodium bicarbonate solution and stirred at -5° for 5 minutes. The reaction mixture is diluted with 200 ml methylene chloride and the phases are separated. The aqueous phase is extracted with 250 ml methylene chloride and the combined organic phases are washed with 3*75 ml portions of water and dried over anhydrous sodium sulfate. The solvent is removed from the rotary evaporator to give 5.8 g (79percent) of 2 as yellow crystals, m.p. 106°-108°.
Reference：
[1] Patent: US4709035, 1987, A,
3
[ 105410-36-4 ]
[ 87885-43-6 ]
Reference：
[1] Journal of Medicinal Chemistry, 1984, vol. 27, # 12, p. 1634 - 1639
With ozone; 3-chloro-benzenecarboperoxoic acid; In dimethyl sulfoxide;
Oxidation of the sulfilimine with MCPBA furnishes the nitro derivative.
0.5 g
To m-chloroperbenzoic acid (8.0g, 0.46 mmol 85%) in dichloromethane(100 mL)(cooled to -5C) was added a solution of S,S-dimethyl-N-(2-pyrazinyl)sulfilimine (5.36 g, 0.028 mmol) in 30ml dichloromethane dorpwise at such a rate for 1 hour with the temperature not exceed 0C, the reaction mixture was stirred for another 40min at 0C, The solution of dimethyl sulfide in dichloromethane was added at 0C. Filltered quickly to afford a orange clean solution .The solution was cooled to -78C, then 03 was bubbled into the mixture until the orange solution was turned to be colorless. The resulting suspension was quenched with sodium dicarbonate solution and then extracted with dichloromethane for three times. The combined organic phase was concentrated to afford the crude product, which was further purified by flash chromatography to afford 2-Chloro-3-nitro-pyrazine. (0.5 g, yield: 7%).1HNMR (DMS0-
Step B: 3-Chloro-2-nitropyrazine (3) To 7.9 g (0.46 mol, 80-90%) m-chloroperbenzoic acid in 70 ml methylene chloride cooled to -5 and stirred mechanically is added a solution of 5.36 g (0.028 mol) 2 in 30 ml methylene chloride dropwise at such a rate that the temperature does not exceed 0. The reaction mixture is stirred at 0 for 40 minutes and then 3 ml of dimethyl sulfide is added with stirring for another 10 minutes at 0. The cold reaction mixture is filtered quickly to afford a clear, green solution of the nitroso derivative. This solution is cooled to 0 and ozone is bubbled through until the solution is nearly colorless. The resulting suspension is extracted with 2*50 ml saturated sodium bicarbonate and the organic phase is dried over anhydrous sodium sulfate. The solvent is removed from the rotary evaporator to give a yellow oil which is purified by flash chromatography on silica gel with chloroform elution. Pure 3 is a pungent, yellow oil.
Step B: 3-Chloro-2-nitropyrazine (3) To 7.9 g (0.46 mol, 80-90%) m-chloroperbenzoic acid in 70 ml methylene chloride cooled to -5 and stirred mechanically is added a solution of 5.36 g (0.028 mol) 2 in 30 ml methylene chloride dropwise at such a rate that the temperature does not exceed 0. The reaction mixture is stirred at 0 for 40 minutes and then 3 ml of dimethyl sulfide is added with stirring for another 10 minutes at 0. The cold reaction mixture is filtered quickly to afford a clear, green solution of the nitroso derivative. This solution is cooled to 0 and ozone is bubbled through until the solution is nearly colorless. The resulting suspension is extracted with 2*50 ml saturated sodium bicarbonate and the organic phase is dried over anhydrous sodium sulfate. The solvent is removed from the rotary evaporator to give a yellow oil which is purified by flash chromatography on silica gel with chloroform elution. Pure 3 is a pungent, yellow oil.
5
[ 5625-67-2 ]
[ 87885-43-6 ]
1-(3-nitro-2-pyrazinyl)piperazin-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6.96 g (54.7%)
With triethylamine; In chloroform; isopropyl alcohol;
EXAMPLE 1 1-(3-Nitro-2-pyrazinyl)piperazin-3-one A solution of <strong>[87885-43-6]2-chloro-3-nitropyrazine</strong> (9.1 g, 57 mmol) in chloroform (100 ml) was added dropwise over 45 minutes to a cooled solution of piperazine-2-one (5.71 g, 57 mmol) and triethylamine (8.0 ml, 57 mmol) in isopropanol (120 ml). After addition was complete, the reaction mixture was allowed to warm to 20-25 and was stirred at this temperature for 20 hours. The precipitate was removed by filtration and recrystallized from methanol-ethyl acetate-hexane to give 6.96 g (54.7%) of product, m.p. 178-179.
1-(3-nitro-2-pyrazinyl)hexahydro-1H-1,4-diazepin-5-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium chloride; triethylamine; In chloroform; ethyl acetate; isopropyl alcohol;
EXAMPLE 2 1-(3-Nitro-2-pyrazinyl)hexahydro-1H-1,4-diazepin-5-one To a solution of hexahydro-1H-1,4-diazepin-5-one (1.14 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in isopropanol (30 ml) cooled in an ice bath, was added over 30 minutes a solution of <strong>[87885-43-6]2-chloro-3-nitropyrazine</strong> (1.59 g, 10 mmol) in chloroform (20 ml). After addition was complete, the reaction mixture was allowed to warm to 20-25 and was stirred at this temperature for 20 hours. Solvents were removed under reduced pressure and the residue was partitioned between a saturated aqueous solution of sodium chloride and ethyl acetate. The ethyl acetate extract was dried over anhydrous sodium sulfate, filtered and concentrated to an oil. Flash chromatography over silica gel and elution with 2% methanol -98% chloroform gave pure 1-(3-nitro-2-pyrazinyl)hexahydro-1H-1,4-diazepin-5-one. STR3
1-(3-nitro-2-pyrazinyl)-4-(2-hydroxyethyl)piperazin-3-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
0.90 g (48.6%)
With sodium chloride; triethylamine; In chloroform; ethyl acetate; isopropyl alcohol;
Step C 1-(3-Nitro-2-pyrazinyl)-4-(2-hydroxyethyl)piperazin-3-one A solution of <strong>[87885-43-6]2-chloro-3-nitropyrazine</strong> (1.59 g, 10 mmol) in chloroform (20 ml) was added over 30 minutes to an icebath cooled solution of 4-(2-hydroxyethyl)piperazin-3-one (1.44 g, 10 mmol) and triethylamine (1.01 g, 10 mmol) in isopropanol (30 ml). After addition was complete, the reaction mixture was allowed to warm to 20-25 and was stirred at this temperature for 20 hours. Solvents were removed under reduced pressure and the residue was partitioned between a saturated aqueous solution of sodium chloride and ethyl acetate. The ethyl acetate extract was dried over anhydrous sodium sulfate, filtered and concentrated to an oil. Flash chromatography over silica gel and elution with 5% methanol-95% chloroform gave 0.90 g (48.6%) of 1-(3-nitro-2-pyrazinyl)-4-(2-hydroxyethyl)piperazin- 3-one. An analytical sample, m.p. 117-120, was obtained upon recrystallization from ethyl acetatehexane.
With dimethyl sulfoxide; trifluoromethanesulfonic acid anhydride; In dichloromethane;
EXAMPLE 1 3-Chloro-2-nitropyrazine STR11 Step A: S,S-Dimethyl-N-(3-chloropyrazin-2-yl)sulfilimine (2) To a mechanically stirred solution of 3.9 g (0.05 mol) dimethyl sulfoxide in 30 ml dry methylene chloride at -78 under nitrogen is added 13.1 g (0.046 mol) trifluoromethanesulfonic anhydride dropwise to afford a white precipitate. To this is added a solution of 5.0 g (0.039 mol) 2-amino-3-chloropyrazine (1) in 30 ml methylene chloride/15 ml dimethyl sulfoxide and the resulting solution is stirred at -78 for 2 hours and at -55 for 1 hour. The reaction mixture is then quenched with 50 ml of 5% aqueous sodium bicarbonate solution and stirred at -5 for 5 minutes. The reaction mixture is diluted with 200 ml methylene chloride and the phases are separated. The aqueous phase is extracted with 250 ml methylene chloride and the combined organic phases are washed with 3*75 ml portions of water and dried over anhydrous sodium sulfate. The solvent is removed from the rotary evaporator to give 5.8 g (79%) of 2 as yellow crystals, m.p. 106-108.
With triethylamine; In 1,4-dioxane; at 70℃;Inert atmosphere;
A mixture of 2-Chloro-3-nitro-pyrazine (0.5 g, 3 mmol) and [l-(4-Amino- phenyl)-cyclobutyl]-carbamic acid tert-butyl ester (0.98 g, 3.6 mmol) in dioxane (20mL) was added Et3N (2ml) in one portion. Then the reaction mixture was warmed to 70C for overnight. Cooled to room temperature and Concentrated to dryness to afford the residue, which was further purified by flash chromatography to afford { l-[4-(3-Nitro-pyrazin-2-ylamino)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester. (0.57 g, 50% yield). LC/MS (ESI+): 386[M+1]+, 388[M+3]+
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